Bisphosphonate drug holidays can lead to significant bone loss and increase the risk of clinical vertebral fractures, resulting in substantial disability and heightened likelihood of hip fractures. Evidence from studies indicates that continuing treatment with bisphosphonates is beneficial for bone health while the risk of atypical femoral fractures remains very low. Overall, the risks associated with stopping treatment far outweigh the rare risks of long-term bisphosphonate use.

1. Patients receiving bisphosphonates should
not take holidays from treatment
Steve Cummings

2. Richard likes holidays

3. Sri Lanka
Scotland
China

4. For tourists, holidays are fun!

5. For patients taking bisphosphonates
drug holidays are dangerous

6. The evidence

7. A randomized trial of holidays
The FLEX Trial*
*Similar conclusions for Zoledronate from the HORIZON extension trial

8. 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

9. Taking a holiday caused hip bone loss
Black et al. JAMA 2008;296:1671

10. 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 -5
Lost BMD
McNabb, et al. JBMR 2013;28:1319–1327

11. A holiday increased bone resorption to
pretreated levels
Black et al. JAMA 2008;296:1671

12. A holiday increased bone resorption to
pretreated levels
Bone structure
deteriorates
Black et al. JAMA 2008;296:1671

13. A holiday increased the risk of clinical
vertebral fracture
0
1
2
3
4
5
6
Continue Holiday
5.5%
2.5%
Black et al. JAMA 2008;296:1671

14. A holiday increased the risk of clinical
vertebral fracture
0
1
2
3
4
5
6
Continue Holiday
5.5%
2.5%
Black et al. JAMA 2008;296:1671
2.9% difference in risk
NNT for 5 years = 38

15. Clinical vertebral fractures cause at least as
many days of disability as hip fractures
110
149
140
78
All types Clinical spine Hip Wrist
Days of limited activity
Based on diaries of women in the placebo groups of the FIT trial
Fink et al. Osteoporos Int 2003;14: 69–76

16. 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

17. A holiday increased the risk of clinical
vertebral fractures regardless of BMD
Schwartz et al. JBMR 2010;25:976-82

18. 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

19. 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

20. What’s the harm of continuing
treatment?
Atypical femoral fractures (AFFs)

21. Atypical femoral fractures (AFF)

22. Fear of AFFs

23. Schilcher et al. (NEJM, 2011)
AFFs are extremely rare
Only 1 AFF for every 200 hip fractures

24. Relative and absolute risk
First, a refresher

25. Average annual risks of dying in the UK
Plane crash
Car crash
http://www.economist.com/blogs/gulliver/2015/01/air-safety

26. Relative risk
Plane crash 1
Car crash 100
http://www.economist.com/blogs/gulliver/2015/01/air-safety
Average annual risks of dying in the UK

27. Relative risk
Plane crash 1
Car crash 100
Should you stop driving?
http://www.economist.com/blogs/gulliver/2015/01/air-safety
Average annual risks of dying in the UK

28. Relative risk Absolute risk
Plane crash 1 1 / 3,500,000
Car crash 100 1 / 35,000
Should you stop driving?
http://www.economist.com/blogs/gulliver/2015/01/air-safety
Average annual risks of dying in the UK

29. Most rigorous studies
• Large studies
• X-ray confirmation
• Definitions related to ASBMR criteria
Studies of the risk of AFF with
long-term use

30. 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

31. Risk of AFF with long-term use
1.7
8.2
28.7
39.7
116.4
0
20
40
60
80
100
120
<1 ≤1-2 ≤2-3 ≤3-4 ≤4-5
Relative Risk of AFF
Schilcher, et al. NEJM 2014;371:974-5

32. 0.00002 0.00008 0.0003 0.0004
0.001
0
0.002
0.004
0.006
0.008
0.01
<1 ≤1-2 ≤2-3 ≤3-4 ≤4-5
Absolute Risk of AFF
Schilcher, et al. NEJM 2014;371:974-5
1%
1.1/1,000
Risk of AFF with long-term use

33. If a patient stops bisphosphonate...
• “70% reduction” in risk of AFF
• From 11/10,00 to 3/10,000
• From rare to rare
Schilcher, et al. NEJM 2014;371:974-5

34. 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
Risk of AFF with long-term use

35. for age
1/1,000 for 10+ years
Dell, et al. JBMR 2012;27:2544-50
Absolute risk of AFF with long-term use

36. Summary so far
In 1,000 patients taking alendronate
Compared with continuing treatment,
taking a 5 year holiday
–Causes 30 clinical vertebral fractures
–Prevents 5 cases of AFF

37. 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

38. A 3-year Zoliday caused
2-fold increased risk of radiographic
vertebral fracture (NNT = 30)
Zoliday Continue
6.2%
3.0%
Cumulative%incidence
ofvertebralfracture
Black et al. JBMR 2012;27:243–254
Very limited data
about other outcomes

39. 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)

40. 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

41. 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

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

43. 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 = 38
Based on Bo Abrahamsen… Richard Eastell. BMJ 2016;353:i3365

44. Dr. Eastell concluded
“The findings support a good benefit : risk
with alendronate in terms of bone health
for over 10 years of continuous use.”
Bo Abrahamsen… Richard Eastell. BMJ 2016;353:i3365

45. Your choice
Vote for Richard Or vote for Dr. Eastell
For the motion Against the motion
Richard the tourist Dr. Eastell, the esteemed
evidence-based clinical scientist

46. Rebuttal

47. 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

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

49. 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

50. 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

51. 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

52. 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

53. 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

54. 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 fracture
All prevented by continuing treatment
• Outweighs a very rare risk of AFF

55. 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 fracture
All prevented by continuing treatment
• Outweighs a very rare risk of AFF
Very limited data makes Zolidays risky

56. Thank you

57. Financial Disclosures
• Consultant to Amgen, Radius, Merck
• United Airlines
– Has given me 1.8 million award miles to use for
holidays

58. No increase in subtrochanteric/femoral shaft
(ST/FS) fractures with 10+ years
AFF’s are 3 to 38%
of ST/FS fractures

59. 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.”
Bo Abrahamsen… Richard Eastell. BMJ 2016;353:i3365

60. 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

61. 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.

62. Benefit of treatment on risk of vertebral
fractures is lost quickly after omitting a
scheduled dose
Cummings, unpublished
Median time off: 3 mo.s

63. Benefit of treatment on risk of vertebral
fractures is lost quickly after omitting a
scheduled dose
Cummings, unpublished

64. Denosumab
• Holidays are dangerous!
• Continue denosumab or immediately switch
to a bisphosphonate.