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
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Osteoporosis 2016 | Patients receiving bisphosphonates should take holidays from treatment Richard Eastell #osteo2016
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Richard Eastell
Director, The Mellanby Centre for Bone Research,
University of Sheffield, UKThe Mellanby Centrefor Bone Research
Patients receiving bisphosphonates
should take holidays from treatment
The case for holidays
Osteoporosis Conference 2016, 8-Nov-2016
My opponent
Dr Steven R Cummings
Conflicts of Interest
• Research funding, consulting and honoraria fromo Novartiso Amgeno AstraZenecao Pfizero Warner Chilcotto Sanofio IDSo Roche Diagnostics
Developing the case for stopping bisphosphonate therapy in osteoporosis: ‘Drug Holiday’
• Why should we consider stopping treatment?o Benefits of bisphosphonate therapy for osteoporosiso Risk of bisphosphonate therapy for osteoporosis
− Atypical femur fracture
• Is it harmful to stop treatment?o Effect on fracture risko Are all bisphosphonates the same?o Mechanism for continued effect on bone turnover
Fosamax (alendronate) hits on Google in USAA, ONJB, atrial fibrillationD, atypical femur fractures (ABC World News)
Jha, et al. J Bone Miner Res; 2015 Dec;30(12):2179-87
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’?
Atypical femur fractures against time on treatment (years)
Dell R, et al. J Bone Miner Res. 2012; 27(12),2544–50
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
Is it harmful to stop treatment?
Black DM…Cummings SR. JAMA. 2006;296:2927–2938.
Effect of Stopping Alendronic Acid on Hip and Spine BMD: FIT and FLEX
Effect of Stopping Alendronic Acid on Fracture Risk: FLEX
Black DM…Cummings SR. JAMA. 2006;296:2927–2938.
No Effect on Morphometric Vertebral Fractures
How Quickly Does Anti-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
Naylor…Eastell. ASBMR Atlanta 2016: MO0291
How Quickly Does BMD Effect Wear off after Stopping Oral Bisphosphonates
Naylor…Eastell. ASBMR Atlanta 2016: MO0291
Thus, after stopping oral bisphosponatesNo BMD loss from the spine, BMD loss from the hipBTM remain reduced after ALL oral bisphosphonates, even after 2 years
Why do bisphosphonates continue to inhibit bone resorption for many years after stopping?
• Mechanism 1o Bisphosphonates bind
to bone− Alendronate more than
risedronateo 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
Problems with Mechanism 1:BPs unmeasurable after stopping treatment
• Alendronate could be measured o in all patients on active treatmento in 41% of 36 patients 14 months after stopping treatment
• Risedronate could be measured o in all patients on active treatmento in 0% of 7 patients 14 months after stopping treatment
Active treatment Prior treatment pAlendronate, 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.
Problems with Mechanism 1:BPs should differ in BTM effect during offset
• Hydroxyapatite adsorption affinity varies by BPo Higher for
zoledronic acid and alendronate
o Lower for risedronate and ibandronate
Nancollas GH, et al. Bone 2006 May;38(5):617-27
Mechanism 2All bisphosphonates reduce osteoclast precursors to a similar extent
• TRIO Studyo 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
What do the UK guidelines say?
Compston J, et al.Maturitas. 2013 Aug;75(4):392-6
What does Dr Cummings recommend?
• …we believe that the current evidence base supports the following conclusionso 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
Patients receiving bisphosphonates should take holidays from treatmentVote for holidays!