Osteoporosis 2016 | Patients receiving bisphosphonates should not take holidays from treatment: Dr Steve Cummings #osteo2016

Patients receiving bisphosphonates should not take holidays from treatment

Steve Cummings

Richard likes holidays

Sri Lanka

Scotland

China

For tourists, holidays are fun!

For patients taking bisphosphonates drug holidays are dangerous

The evidence

A randomized trial of holidays

The FLEX Trial*

*Similar conclusions for Zoledronate from the HORIZON extension trial

FLEX

• 1099 women who received 4-5 years of alendronate

• Randomized to stop or continue to 10 years

Black et al. JAMA 2008;296:1671

Taking a holiday caused hip bone loss


A holiday caused rapid hip bone loss

• Stopped alendronate after 4-5 years

• On average, lost 3.6% of total hip BMD in 5 years

• 29% lost >5%!• Some lost >10%• Could not predict

who would lose

-15 -10 -5Lost BMD

McNabb, et al. JBMR 2013;28:1319–1327

A holiday increased bone resorption to pretreated levels


A holiday increased bone resorption to pretreated levels

Bone structure deteriorates


A holiday increased the risk of clinical vertebral fracture

Continue Holiday0

1

2

3

4

5

6 5.5%

2.5%


A holiday increased the risk of clinical vertebral fracture

Continue Holiday0

1

2

3

4

5

6 5.5%

2.5%


2.9% difference in riskNNT for 5 years = 38

Clinical vertebral fractures cause at least as many days of disability as hip fractures

All types Clinical spine Hip Wrist

110

149 140

78

Days of limited activity

Based on diaries of women in the placebo groups of the FIT trialFink et al. Osteoporos Int 2003;14: 69–76

Holidays may cause disability

For 1000 patients in FLEX• Overall, a 5-year holiday• Caused 30 clinical vertebral fractures• Caused about 12 years (4,500 days) of disability• Prevented by continuing alendronate

A holiday increased the risk of clinical vertebral fractures regardless of BMD

Schwartz et al. JBMR 2010;25:976-82

Treat 81 to prevent a clinical vertebral fracture

Even in patients with hip T-scores >-2.0

Schwartz et al. JBMR 2010;25:976-82

Holidays may cause disability

For 1000 “low risk” patients in FLEX• A holiday caused • 12 clinical vertebral fractures• About 5 years (~1,800 days) of disability.• Prevented by continuing alendronate

What’s the harm of continuing treatment?

Atypical femoral fractures (AFFs)

Atypical femoral fractures (AFF)

Fear of AFFs

Schilcher et al. (NEJM, 2011)

AFFs are extremely rare

Only 1 AFF for every 200 hip fractures

Relative and absolute risk

First, a refresher

Average annual risks of dying in the UK

Plane crash

Car crash

http://www.economist.com/blogs/gulliver/2015/01/air-safety

Relative risk

Plane crash 1

Car crash 100



Relative risk

Plane crash 1

Car crash 100

Should you stop driving?



Relative risk Absolute risk

Plane crash 1 1 / 3,500,000

Car crash 100 1 / 35,000

Should you stop driving?



Most rigorous studies• Large studies• X-ray confirmation• Definitions related to ASBMR criteria

Studies of the risk of AFF with long-term use

Risk of AFF with long-term use

Schilcher, • Women & men 55+ y.o. with a femoral fracture • Radiographs of femoral fracture for 5,342• 172 patients had AFFs by ASBMR criteria. • Bisphosphonate use from national registry

Schilcher, et al. NEJM 2014;371:974-5


<1 ≤1-2 ≤2-3 ≤3-4 ≤4-50

20

40

60

80

100

120

1.7 8.2

28.739.7

116.4Relative Risk of AFF


<1 ≤1-2 ≤2-3 ≤3-4 ≤4-50

0.0010.0020.0030.0040.0050.0060.0070.0080.009

0.01

0.00002 0.00008 0.0003 0.0004 0.001

Absolute Risk of AFF


1%

1.1/1,000


If a patient stops bisphosphonate...

• “70% reduction” in risk of AFF• From 11/10,00 to 3/10,000• From rare to rare


Dell• Kaiser Health System: ~1.8 million patients• Women & men 45+ y.o. with a femur fracture • Radiographs for 5,342• 142 patients had AFFs by ASBMR criteria. • Bisphosphonate use from pharmacy records

Dell, et al. JBMR 2012;27:2544-50


for age

1/1,000 for 10+ years

Dell, et al. JBMR 2012;27:2544-50

Absolute risk of AFF with long-term use

Summary so far

In 1,000 patients taking alendronateCompared with continuing treatment, taking a 5 year holiday–Causes 30 clinical vertebral fractures–Prevents 5 cases of AFF

Randomized trial of a 3 year holiday from zoledronate (Zoliday)

• Zoledronate is used by <10% • 1233 randomized to stop after 3 or continue 3

more• A 3-year holiday caused 1.5% loss of FN BMD

and 2.1% loss of L-spine BMD– ~50% will lose more, not predictable

Black et al. JBMR 2012;27:243–254

A 3-year Zoliday caused

2-fold increased risk of radiographicvertebral fracture (NNT = 30)

Zoliday Continue

6.2%

3.0%

Cum

ulati

ve %

inci

denc

e o

f ver

tebr

al fr

actu

re

Black et al. JBMR 2012;27:243–254

Very limited data about other outcomes

Effect of holidays from alendronate on nonvertebral fractures?

• FLEX was not designed and did not have statistical power to detect an important reduction in risk of nonvertebral fractures.

• No power to determine whether continuing treatment reduced the risk of hip fracture

(95% CI, 0.76-1.32)

Stronger evidence

• 61,990 alendronate users in Denmark• 2465 took alendronate for 10+ years with high

adherence (MPR ≥ 0.80)• 2 nested case-control studies to estimate the

effect of alendronate on fracture risk• Studied subtrochanteric and femoral shaft

fractures (3 to 38% are AFFs)• Adjusted for many potential confounders

Bo Abrahamsen… Richard Eastell. BMJ 2016;353:i3365d

Evidence from Dr. Eastell et al.Continuing alendronate for >5 or ≥10 years

reduces hip fracture by an ~25%

Bo Abrahamsen… Richard Eastell. BMJ 2016;353:i3365

Hip fracturesST/FS fractures

During 10+ years, the rate of ST/FS fractures remained much lower than hip fracture

In 1,000 patients taking alendronate for 5 years

Compared with continuing for 5 more years, a holiday would • cause 26 hip fractures• prevent 1 ST/FS fracture (<1 AFF)

*NNT for 5+ years = 38Based on Bo Abrahamsen… Richard Eastell. BMJ 2016;353:i3365

Dr. Eastell concluded

“The findings support a good benefit : risk with alendronate in terms of bone health for over 10 years of continuous use.”


Your choiceVote for Richard Or vote for Dr. Eastell

For the motion Against the motion

Richard the tourist Dr. Eastell, the esteemed evidence-based clinical scientist

Rebuttal

Other problems with holidays

• Holidays from treatment creates a mistaken impression that treatment is bad

• If patients expect holidays, those who need to continue will be very disappointed

• If patients take a holidays, they may never come back

Zoledronate

• >90% of patients receive alendronate• Arguments about zoledronate apply to <10%

of patients

3- year Zoliday

• Confidence intervals are very wide for– Nonvertebral (0.7 to 1.5), – Clinical vertebral (0.5 to 6.2)– Hip 0.3 to 2.5).

• We need a much large study (in Denmark) – Expect a similar result as alendronate: significant

reductions in hip fracture for 10+ years

High risk patients taking zoledronate

• Total hip T-score <-2.5 indicates a higher risk of vertebral and nonvertebral fractures

• Greater absolute reductions in risk of vertebral fractures

• For moderate risk patients, very wide confidence intervals– Decreased risk of vertebral fracture with TH >-2.5:

0.79 (0.3 to 2.5)• Too little data for nonvertebral and hip fracture

Cosman et al. J Clin Endocrinol Metab 2014; 99: 4546–4554

Uncertainty about Zolidays

• We said: “after 3 years of annual ZOL, many patients may discontinue therapy up to 3 years.”

• Based on very little data, especially in moderate risk patients.

• A lot of uncertainty and, therefore, zolidays are risky

IOF Epidemiology/Quality of Life Working Group

• Voted on appropriateness of bisphosphonate holidays

• The voting revealed considerable controversy globally and a lack of consensus on identification, management, and monitoring of antiresorptive holidays.

Silverman et al. IOF Epidemiology/Quality of Life Working Group.Osteoporos Int (2016) 27:849–852

IOF Epidemiology/Quality of Life Working Group

• Taking account of ONJ• Women with T-score <-2.5 or a vertebral

fracture, prevent 7 to 35 clinical vertebral fracture for every event of ONJ or AFF

• “… a postive risk/benefit ratio for high risk women.”

Silverman et al. IOF Epidemiology/Quality of Life Working Group.Osteoporos Int (2016) 27:849–852

The case against holidays

Holidays • Cause substantial hip bone loss • Increase bone resorption• Increase the risk of clinical vertebral fractures – With substantial disability

• Increase the risk of hip fractureAll prevented by continuing treatment• Outweighs a very rare risk of AFF

The case against holidays

Holidays • Cause substantial hip bone loss • Increase bone resorption• Increase the risk of clinical vertebral fractures – With substantial disability

• Increase the risk of hip fractureAll prevented by continuing treatment• Outweighs a very rare risk of AFFVery limited data makes Zolidays risky

Thank you

Financial Disclosures

• Consultant to Amgen, Radius, Merck• United Airlines– Has given me 1.8 million award miles to use for

holidays

No increase in subtrochanteric/femoral shaft (ST/FS) fractures with 10+ years

AFF’s are 3 to 38% of ST/FS fractures

A limitation of the Abrahamsen…Eastell study

• No radiographs for AFFs• The study used ST/FS fractures, not AFFs• “Even in the worst case scenario (100% of

ST/FS are atypical and secondary to bisphosphonate use…) the number of atypical femur fractures remains too low to offset the benefits on hip fracture in patients with long term alendronate use up to 10 years.”


Does the risk of AFF increase with longer use?

for age

No reason to ‘adjust for age’ because there was no association of incidence of AFF with age

Dell, et al. JBMR 2012;27:2544-50

Denosumab

• Bone mass continues to improve• Vertebral fracture risk remains low on

treatment• A ‘holiday’ increases vertebral fracture risk to

untreated levels• Increased risk of multiple vertebral fractures• Happens within 3 months of skipping a

scheduled dose.

Benefit of treatment on risk of vertebral fractures is lost quickly after omitting a

scheduled dose

Cummings, unpublished

Median time off: 3 mo.s

Benefit of treatment on risk of vertebral fractures is lost quickly after omitting a

scheduled dose

Cummings, unpublished

Denosumab

• Holidays are dangerous!• Continue denosumab or immediately switch

to a bisphosphonate.

Healthcare

Osteoporosis 2016 | Patients receiving bisphosphonates should not take holidays from treatment: Dr Steve Cummings #osteo2016