Antiresorptive therapy : when to

start? When to have a drug Holiday?

Jean-Marc Kaufman

Endocrinologie UZGent jean.kaufman@ugent.be

BMS Brussels October 14th 2017

• No potential conflicts of interest to declare

Long term management of osteoporosis: why? A disorder throughout the life course

~50% of hip fracture patients have experienced prior fractures

Kanis JA & Johnell O. J Endocrinol Invest 1999;30:583-588

Age, lower BMD and prior fracture are major risk factors so that

fracture risk will increase and morbidity accumulate if untreated.

Nele 1

Mother hipfracture at age 83y

No fracture history; no other risk facors

Nele then 54y had a DXA:

T-score L1-L4: -2.7

T-score femoral neck: -2.0

T-score total hip: -0.7

R/ calcium+vit D & raloxifene, after 3 months stop

(VMS, leg cramps) and changed to

alendronate 70mg/week

Now 61y; 6,5y alendronate; GP asks advise

further management

Laura Wrist fracture at age 52y

Clinical fracture D12 at age 72y

RX: fracture D12 and old fracture D7

Past smoker; COPD Gold II

46kg; 162 cm (BMI 17,5)

DXA

T-score L1-L4: -3.7

T-score femoral neck: - 3.0

R/ calcium+vitD; alendronate 70mg/week

Now 77j; 5 years alendronate

Further treatment?

Kristel 1

Non traumatic fracture D10 at age 61y

Surgical menopause at 44y;

smoking; reflux (R/ PPI)

62kg; 167 cm

DXA

T-score L1-L4: -3.4

T-score femoral neck -2.8

R/ calcium + vitamine D; risedronate 35mg/week

Now 66jaar; risedronate 5years. Further?

Long-term management of osteoporosis

• Is long-term treatment efficacious?

• Is long-term treatment safe?

• What happens when treatment is discontinued?

• Prolonged treatment for whom? How long?

• What are the alternatives?

• Practical approach?

Long-term (7yrs) effects of risedronate

Mellström et al Calcif Tissue Int 2004:75:462-468

urinary NTX Total hip BMD

Annualized vertebral

fracture incidence

BMD = bone mineral density.

Adapted from Bone HG, et al. N Engl J Med. 2004;350:1189–1199. FOSAMAX® (alendronate) is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.

0

2

4

6

8

10

12

14 Spine (P<0.001)

Mean

(±S

E)

% C

han

ge

0

Year

1 2 3 4 5 6 7 8 9 10

(P<0.001)

Hip Trochanter

(P<0.001)

n=196 n=151 n=122 n=86

alendronate 10 mg daily

Long-term effects of alendronate on BMD

Eigth vs five years denosumab in women with

postmenopausal osteoporosis

CTX ng/ml BMD % change from baseline Yearly incidence%

Papapoulos et al Osteoporosis Int 2015;26:2773-83

Denosumab vs placebo in women on aromatase

inhibitor for non metastatic breast carcinoma

Percentage risk of fracture based on Kaplan–Meier time-to-event analysis within each treatment group at 6-month intervals. The HR and P value were calculated from a Cox model including

treatment groups as the independent variable and stratified by the randomisation stratification factors. Error bars are 95% CIs. CI, confidence interval; HR, hazard ratio.

HR = 0.50 (95% CI: 0.39–0.65)

P < 0.0001

Percentage risk of fracture

Placebo

Denosumab

36 30 42 12 6 18 24 0 0

5

10

15

20

25

30

Ris

k o

f fr

ac

ture

(%

)

48

Months since randomisation

54 60 66 72

Number at risk

Placebo 1709 1660 1470 1265 1069 921 785 637 513 384 275 185 112

Denosumab 1711 1665 1488 1297 1118 965 823 688 549 432 305 221 116

Overall cumulative incidence of first clinical fractures

Placebo: n = 176

Denosumab: n = 92

Gnant M, et al. Lancet 2015;386:433–43.

Persistence for alendronate therapy (Belgium)

Persistence of 39% at 12 months

For each % decrease in persistence, 0.4% increase in hip fracture risk

Rabenda et al Osteoporosis Int 2008;19:811

Effect of poor bisphosphonate adherence on

fracture risk (Meta-analysis)

≤80% compliance:

Fracture risk +46%

vertebral +43%

Hip +28%

Non-vertebral +16%

Imaz et al Osteoporos Int 2010;21:1943-51

Risks associated with prolonged strong suppression of bone turnover?

Adapted from Weinstein RS, J Bone Miner Res 2000; 15 621.

Physiological Range

Bo

ne

Str

en

gth

Bone Turnover

Excessive turnover

• Increase in stress risers (weak zones)

• Increase in perforations

• Loss of connectivity

Insufficient turnover

• Accumulation of microdamage

• Increased brittleness due to

excessive mineralization

? Osteoporosis

Potential adverse effects?

• Acute phase reactions

• Gastroesophageal irritation

• Impaired renal function

• Hypocalcemia

• Infections??

• Atrial fibrillation ??

• Oesophageal cancer??

• Cardiovascular disease??

• Osteonecrosis of the jaw (ONJ)

• Atypical femoral fracture (AFF)

Osteonecrosis of the jaw (ONJ)

• Exposed necrotic bone in maxillofacial region for at least 8 weeks of

appropriate treatment.

• No history of radiation therapy to the jaw

• Increased risk associated with use of potent antiresorptive agents

(bisfosfonates;denosumab) and anti-angiogenic agents

• Mostly in cancer patients on high dose BP or denosumab

• Risk factors: glucortocoids; poor oral hygiene; diabetes; smoking

• Estimated incidence under

treatment with bisphosphonates

for osteoporosis:

1/10,000 to 1/100,000 patient

treatment years*

• No clear indication for treatment

duration effect

*Khosla et al J Bone Miner Res 2007;22:1479-91

(JBMR 2010)

Atypical femoral fracture (AFF)

• Subtrochanteric + at least 4 out of 5 major diagnostic criteria

(besides not obligatory minor criteria)

• Indication for bisphosphonate exposure duration relationship

• Age-adjusted incidence rate*:

1.8/100,000 per year

with a 2y BP exposure

to

113/100,000 per year with

8 to 9.9y BP exposure

*Dell et al J Bone Miner Res 2012;27:2544-50

Bisphosphonate use-associated risks into perspective

Adler et al J Bonne Miner Res 2016; 31: 16-35 (Task Force ASBMR)

Treatment with BP for 5 years:

175 hip fractures, 1470 vertebral fractures, 945 wrist fractures (total: 2590)

potentially averted for risk of 16 AFF

What happens after discontinuation?

• Drugs that work

while you take them: – Calcium/vitamin D

– HRT

– Raloxifene

– Denosumab

– Teriparatide

• Bisphosphonates:

– What do we learn from the

FLEX (FIT extension) trial? –

alendronate offset

– What do we learn from the

HORIZON extension trial? –

zoledronic acid offset

– Other bisphosphonates?

0

2

4

12

14

16

0 1 2 3 4

BM

D C

ha

ng

e F

rom

FIT

Ba

se

lin

e, M

ea

n %

b

Year

FIT FLEX 3.7%

P<0.001

6

8

10

0

2

4

12

14

16

0 1 2 3 4

Year

6

8

10

5

Number

FOSAMAX/FOSAMAX 662 660 658 656 460c 657 642 628 599 580 553

FOSAMAX/placebo 437 435 436 432 297c 437 428 415 401 380 361

Fit long term extension (FLEX) trial

Alendronate 5/10mg/day 5yrs followed by

randomization to alendronate 10mg/day or placebo

Lumbar Spine

Black et al JAMA 2006;296:2927

Year Year

alendronate/alendronate alendronate/placebo

Fit long term extension (FLEX) trial

0

2

4

12

14

16

0 1 2 3 4

BM

D C

ha

ng

e F

rom

FIT

Ba

se

lin

e, M

ea

n %

b

Year

FIT FLEX

2.4%

P<0.001

6

8

10

0

2

4

12

14

16

0 1 2 3 4

Year

6

8

10

5

Number

FOSAMAX/FOSAMAX 662 660 658 656 460c 657 642 628 599 580 553

FOSAMAX/placebo 437 435 436 432 297c 437 428 415 401 380 361

Total Hip

Black et al JAMA 2006;296:2927

alendronate/alendronate alendronate/placebo

Year Year

Small reduction in lumbar spine BMD during off treatment period, while total hip BMD

returned to pre-treatment baseline value after 5 years of ALN discontinuation.

0

0.05

0.10

0.15

0.20

0.25

0 1 2 3 4

Me

an

Va

lue

, n

g/m

Lb

Year

FIT FLEX

0 1 2 3 4

Year

5 Number

alendronate/alendronate 129 57c 45d 129 124 129

alendronate/placebo 87 48c 32d 87 87 87

0

0.05

0.10

0.15

0.20

0.25

55,6%

P<0.001

Fit long term extension (FLEX) trial

Serum CTX (bone resorption marker)

alendronate/alendronate alendronate/placebo

Black et al JAMA 2006;296:2927

Fra

ctu

re I

ncid

en

ce, %

Clinical Vertebral Vertebral Morphometric Nonvertebral 0

RR=0.86

95% CI (0.60, 1.22)

RR=1.00

95% CI (0.76, 1.32)

5.3%

2.4%

11.3% 9.8%

18.9% 19.0%

RR=0.45

95% CI (0.24, 0.85)

5

10

15

20

25 alendronate/alendronate (n=662)

alendronate/placebo (n=437)

Fit long term extension (FLEX) trial

Fracture incidence during extension

Black et al JAMA 2006;296:2927

Fit long term extension (FLEX) trial: prediction of clinical fracture after alendronate

discontinuation (post-hoc analyses)

Age, per 5 y increase:

RR 1.54 (1.26-1.85)

Bauer et al JAMA 2014;174:1126-34

Z6 n= 589 609 608 600 524 450

Z3P3 n= 599 613 606 602 540 467

Time (Years From Core Study Baseline)

Z6 Z3P3

0

Core + Extension study

–2.0

–1.0

0.0

1.0

2.0

3.0

4.0

–3.0

5.0

Start of extension trial

3 6 1 2 4 5

1.36%P < 0.0007 +4.5%

+3.1%

Horizon extension trial: femoral neck BMD

Black et al J Bone and Min Res 2012;27:243-254

Percentage Change (%)

Horizon extension trial: serum P1NP

• Mean values remained within the premenopausal reference range throughout

0

20

40

60

0 1 2 3 4 5 6 Time (years)

Mean

seru

m P

1N

P

(n

g/

mL)

Start of extension trial

Z6 Z3P3

* *

Black et al J Bone and Min Res 2012;27:243-254

Horizon extension trial:

fracture rates during extension

Black et al J Bone and Min Res 2012;27:243-254

Power 99% Power 33%

Morphometric vertebral fractures Non-vertebral fractures

Incident Morphometric Vertebral Fracture Rates: Stratification by FN BMD

FN BMD ≤-2.5

Z3P3 Z6

FN BMD >-2.5

BMD, bone mineral density; CI, confidence interval; FN, femoral neck;

NNT, number needed to treat; OR, odds ratio

3.0%

(7/235) 2.4%

(5/210)

OR: 0.79 (95% CI: 0.23, 2.53)

P = 0.70

3.5%

(9/257)

9.2%

(23/250)

OR: 0.36 (95% CI: 0.15, 0.77)

P = 0.01

0

5

10

15

NNT = 18

NNT = 167

Pro

po

rtio

n o

f P

ati

en

ts (

%)

Treatment subgroup interactions not significant

Cosman et al J Clin Endocrinol Metab 2014;99:4546-54

Incident Morphometric Vertebral Fracture Rates Stratification by Incident Vertebral Fracture During Core Study

CI, confidence interval; NNT, number needed to treat; OR, odds ratio

Differences between Z6 and Z3P3 groups were analyzed using Fisher’s exact test for categorical variables

Incident Vertebral

Fracture During Core

Z3P3 Z6

5.6%

(26/467) 2.6%

(12/454) NA

(0/11)

25%

(4/16)

0

10

20

30

OR: 0.46 (95% CI: 0.22, 0.90)

P = 0.03

P = 0.12

NNT = 4

NNT = 34

Pro

po

rtio

n o

f P

ati

en

ts (

%)

No Incident Vertebral

Fracture During Core

Treatment subgroup interactions not significant

Cosman et al J Clin Endocrinol Metab 2014;99:4546-54

Horizon extension trial:

6 or 9 y of treatment

P1NP

βCTX

Total Hip

Femoral Neck

Black J Bone Miner Res 2015;30:934-44

Offset after 7 years of risedronate

Eastell et al, J Clin Endocrinol Metab. 2011 96: 3367–3373.

Effects of denosumab

treatment and discontinuation

Bone et al J Clin Endocrinol Metab 2011;96:972-80

Effects of denosumab

treatment and discontinuation

Bone et al J Clin Endocrinol Metab 2011;96:972-80

Practical approach to

long-term management?

Key questions for an individualized approach

• What was the baseline fracture risk?

• What is the present treatment?

• How good is the adherence to this treatment?

• What is the reassessed present fracture risk?

Recent incident fracture? FN T-score ≤ -2.5?

drugs affecting bone? Falls? secondary causes?

country-specific FRAX?

Management of postmenopausal women on

long-term bisphosphonate therapy

Adler et al, JBMR, 31, 16-35 (2016) (ASBMR Task Force)

Some limitations

• Based on data Caucasian postmenopausal

women only

• Based on data with alendronate and zoledronic

acid only

• No data beyond 10 years

• No data on the effect on fracture of switching to

another therapy

• Need for more validation of tools such as FRAX

for reassessment of risk under treatment

• No validated criteria for decision if/when to

reinstate treatment following drug holiday

Nele 1

Mother hipfracture at age 83y

No fracture history; no other risk facors

Nele then 54y had a DXA:

T-score L1-L4: -2.7

T-score femoral neck: -2.0

T-score total hip: -0.7

R/ calcium+vit D & raloxifene, after 3 months stop

(VMS, leg cramps) and changed to

alendronate 70mg/week

Now 61y; 6,5y alendronate; GP asks advise

further management

Nele 2

healthy; 58kg; 164cm

No clinical fractures

No new risk factors

DXA:

T-score L1-L4: - 2.1

T-score femoral neck: -1.8

T-score total hip: -0.4

Screening vertebral fracture (IVA): negative

Nele 3

FRAX (including DXA) original at start treatment:

Major osteoporotic fracture: 7,5%/10j

Hip fracture: 1.2%/10j

FRAX (including DXA) present (?) Major osteoporotic fracture: 10%

Hip fracture: 1.1%

Laura 1 Wrist fracture at age 52y

Clinical fracture D12 at age 72y

RX: fracture D12 and old fracture D7

Past smoker; COPD Gold II

46kg; 162 cm (BMI 17,5)

DXA

T-score L1-L4: -3.7

T-score femoral neck: - 3.0

R/ calcium+vitD; alendronate 70mg/week

Now 77j; 5 years alendronate

Further treatment?

Laura 2

RX: fractures D7, D11 & D12

COPD Gold III ; 46kg 161cm

DXA

T-score L1-L4: -2.9

T-score femoral neck: - 2.4

FRAX original:

Major osteoporotic fracture 22%/10j

Hip fracture 9.1%/10j

Kristel 1

Non traumatic fracture D10 at age 61y

Surgical menopause at 44y;

smoking; reflux (R/ PPI)

62kg; 167 cm

DXA

T-score L1-L4: -3.4

T-score femoral neck -2.8

R/ calcium + vitamine D; risedronate 35mg/week

Now 66jaar; risedronate 5years. Further?

Kristel 2 In general few problems

(R/ PPI and lisinopril)

60kg; 167 cm

DXA

T-score L1-L4: -3.0

T-score femoral neck: -2.6

screening vertebral fracture (IVA): D10

FRAX initial:

Major fracture: 20%

Hip fracture: 11%

Research needs and future directions

• Validation of tools for reassessment of

fracture risk under treatment

• More long-term / offset fracture reduction

data needed

• Effects of combined/sequential treatments

• Alternative treatment regimens for

available compounds

Effect of single-dose (5mg) zoledronic acid

in frail elderly women

Greenspan et al JAMA Intern Med 2015;&è(:913-21

Effects over 5yrs of a single dose (5mg) zoledronic

acid in osteopenic postmenopausal women

Grey et al Bone 2012;50:1389-93

βCTX

P1NP

BMD Spine

BMD

Total Hip

BMD

Total Body

Take Home Messages

• Treatment should not be initiated unless

sufficiently high fracture risk

• Poor adherence to treatment is a major problem

• Reassessment after 3 to 5 years is recommended

• Further management is mainly dependent on risk

profile of the patient and which drug she/he is on

• Concerns for risk of feared adverse events (ONJ &

AFF) during long-term treatment should play only

a secondary role in decision making.

Thank you