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

• What do the UK guidelines say?

Why should we consider stopping treatment?

Bisphosphonates Reduce Fracture Risk

Khosla S, et al. J Clin Endocrinol Metab 97: 2272–2282, 2012

Safety and Long-Term Treatment with Bisphosphonates - Concerns

• Safety issueso Atypical femur fractureo Osteonecrosis of the jawo 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 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!