Prof. Richard Eastell's presentation from Osteoporosis 2016: Patients receiving bisphosphonates should take holidays from treatment. The case for holidays. Find out more at: https://nos.org.uk/conference

1. Richard Eastell
Director, The Mellanby Centre for
Bone Research,
University of Sheffield, UK
The
Mellanby
Centre
for Bone Research
Patients receiving
bisphosphonates should
take holidays from
treatment
The case for holidays
Osteoporosis Conference 2016, 8-Nov-2016

2. My opponent
Dr Steven R Cummings

3. Conflicts of Interest
• Research funding, consulting and honoraria from
o Novartis
o Amgen
o AstraZeneca
o Pfizer
o Warner Chilcott
o Sanofi
o IDS
o Roche Diagnostics

4. Developing the case for stopping bisphosphonate
therapy in osteoporosis: ‘Drug Holiday’
• Why should we consider stopping treatment?
o Benefits of bisphosphonate therapy for osteoporosis
o Risk of bisphosphonate therapy for osteoporosis
− Atypical femur fracture
• Is it harmful to stop treatment?
o Effect on fracture risk
o Are all bisphosphonates the same?
o Mechanism for continued effect on bone turnover
• What do the UK guidelines say?

5. Why should we consider stopping
treatment?

6. Bisphosphonates Reduce Fracture Risk
Khosla S, et al. J Clin Endocrinol Metab 97: 2272–2282, 2012

7. Safety and Long-Term Treatment with
Bisphosphonates - Concerns
• Safety issues
o Atypical femur fracture
o Osteonecrosis of the jaw
o Atrial fibrillation (i.v.)
o Others
− Oesophagitis (oral)
− Iritis
• Minimising safety
concerns
Khosla S, et al. J Clin Endocrinol Metab 97: 2272–2282, 2012
Fosamax (alendronate) hits on Google in USA
A, ONJ
B, atrial fibrillation
D, atypical femur fractures (ABC World News)
Jha, et al. J Bone Miner Res; 2015 Dec;30(12):2179-87

8. Atypical Fractures of the Femur Have Been
Associated with Long-term Bisphosphonate
Therapy
• Fracture of the subtrochanteric region or femoral shaft
• Transverse of short oblique orientation
• Minimal trauma
• Medial spike
• No comminution
Can we limit the risk by using
‘Drug Holidays’?

9. Atypical femur fractures against time on
treatment (years)
Dell R, et al. J Bone Miner Res. 2012; 27(12),2544–50

10. Normalised changes over time in
bisphosphonate prescriptions and femur
fractures (subtrochanteric and diaphysial)
Jha, et al. J Bone Miner Res; 2015 Dec;30(12):2179-87

11. Is it harmful to stop treatment?

12. Black DM…Cummings SR. JAMA. 2006;296:2927–2938.
Effect of Stopping Alendronic Acid on Hip
and Spine BMD: FIT and FLEX

13. Effect of Stopping Alendronic Acid on Fracture
Risk: FLEX
Black DM…Cummings SR. JAMA. 2006;296:2927–2938.
No Effect on Morphometric
Vertebral Fractures

14. How Quickly DoesAnti-resorptive Effect Wear off
after Stopping Oral Bisphosphonates
• 57 women with
postmenopausal
osteoporosis
• Treated for 2 years with
oral ibandronate (blue),
alendronate (green) or
risedronate (red)
• Treatments stopped for
two years
0 12 48 96 120 144 168 192
-100
-75
-50
-25
0
week
%changefrombaseline
CTX
Treatment
Offset
0 12 48 96 120 144 168 192
-100
-75
-50
-25
0
week
%changefrombaseline
PINP
Treatment
Offset Ibandronate
Alendronate
Risedronate
Naylor…Eastell. ASBMR Atlanta 2016: MO0291

15. How Quickly Does BMD Effect Wear off
after Stopping Oral Bisphosphonates
Naylor…Eastell. ASBMR Atlanta 2016: MO0291
Thus, after stopping oral bisphosponates
No BMD loss from the spine, BMD loss from the hip
BTM remain reduced after ALL oral bisphosphonates, even after 2 years
0 12 48 96 120 144 168 192
-5
0
5
10
week
%changefrombaseline
TH BMD
Treatment Offset
0 12 48 96 120 144 168 192
-5
0
5
10
week
%changefrombaseline
LS BMD
Treatment Offset
Ibandronate
Alendronate
Risedronate

16. Why do bisphosphonates continue to inhibit
bone resorption for many years after stopping?
• Mechanism 1
o Bisphosphonates bind
to bone
− Alendronate more than
risedronate
o They are taken up by
the osteoclast and
inhibit bone resorption
o The half life of
alendronate is
estimated at 10 years
Baron R, et al. Bone. 2011 Apr 1;48(4):677-92

17. Problems with Mechanism 1:
BPs unmeasurable after stopping treatment
• Alendronate could be measured
o in all patients on active treatment
o in 41% of 36 patients 14 months after stopping treatment
• Risedronate could be measured
o in all patients on active treatment
o in 0% of 7 patients 14 months after stopping treatment
Active treatment Prior treatment p
Alendronate,
ug/day
350 (191) 15 (7) <0.001
Risedronate,
ug/day
93 (63) Not detected
Peris P, et al. Bone. 2011 Oct;49(4):706-9.

18. Problems with Mechanism 1:
BPs should differ in BTM effect during offset
• Hydroxyapatite
adsorption affinity
varies by BP
o Higher for
zoledronic acid and
alendronate
o Lower for
risedronate and
ibandronate
Nancollas GH, et al. Bone 2006 May;38(5):617-27

19. Mechanism 2
All bisphosphonates reduce osteoclast
precursors to a similar extent
• TRIO Study
o Osteoblast
precursors reduced
by ibandronate
(Iband), alendronate
(Alen) and
risedonate (Rise)
o Measured at weeks
0, 1 and 48
Gossiel…Eastell. Bone; 2016 Aug 12;92:94-99
* **
P = 0.02 P = 0.003

20. What do the UK guidelines say?

21. Compston J, et al.
Maturitas. 2013 Aug;75(4):392-6

22. What does Dr Cummings recommend?
• …we believe that the current evidence base supports the
following conclusions
o Patients with low bone mineral density at the femoral neck (T
score below −2.5) after 3 to 5 years of treatment are at the highest
risk for vertebral fractures and therefore appear to benefit most
from continuation of bisphosphonates
o Patients with an existing vertebral fracture who have a somewhat
higher (although not higher than −2.0) T score for bone mineral
density may also benefit from continued therapy
o Patients with a femoral neck T score above −2.0 have a low risk
of vertebral fracture and are unlikely to benefit from continued
treatment
Black DM...Cummings SR... N Engl J Med; 2012 May 31;366(22):2051-3

23. Patients receiving
bisphosphonates should take
holidays from treatment
Vote for holidays!