Advances in osteoporosis treatment

1
Advances in osteoporosis treatment

• John C Stevenson
• National Heart Lung Institute
• Imperial College London
• Royal Brompton Hospital
• London, UK

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PREVENTION TREATMENT
anti-resorptive
bone formation

• HRT
• tibolone
• SERMs
• bisphosphonates
• strontium
• calcitonin

• teriparatide
• ? strontium
• ? HRT

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HRT RISKS

• breast cancer
• inconclusive for E P
• no increase with E alone
• stroke
• dose / route
• no increase if HRT initiated below age 60 years
• venous thrombo-embolism
• dose / route
• transient increase seen with oral HRT
• no increase with transdermal HRT

Stevenson et al. Atherosclerosis 2009 207 336-40
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BISPHOSPHONATES RISKS

• gastro-intestinal side-effects
• atrial fibrillation
• more severe with IV bisphosphonates
• osteonecrosis of the jaw
• more common with IV bisphosphonates
• follows dental extractions only
• inflammatory eye disease
• only with IV bisphosphonates
• oesophageal cancer
• only with oral bisphosphonates
• taken for gt3 years
• femoral stress fractures
• long term bisphosphonates

Heckbert et al. Arch Intern Med 2008 168
826-31 Seghizadeh et al. J Am Dent Assoc 2009
140 61-66 Sharma et al. N Engl J Med 2008 359
1410-11
Green et al. BMJ 2010 341 c4444 Schilcher et
al. N Engl J Med 2011 364 1728-37
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NEW TREATMENT APPROACHES

• target signalling systems to bone cells
• target cellular action of bone cells

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OSTEOCLAST REGULATION
PTH
estrogen
1,25 (OH)2D
M-CSF
calcitonin
TRAP
cathepsin K
RANK-L
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OSTEOCLAST REGULATION
PTH
estrogen
1,25 (OH)2D
M-CSF
calcitonin
TRAP
cathepsin K
RANK-L
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DENOSUMAB AND FRACTURES
denosumab
placebo

• 7.868 osteoporotic women
• mean age 72.3 years
• randomised to denosumab 60 mg 6-monthly or
  placebo
• studied over median 3 years
• radiographic vertebral fracture HR 0.32
  (CI 0.26-0.41)
• clinical hip fracture HR 0.60 (CI 0.37-0.97)

plt0.001
plt0.05
Cummings et al. N Engl J Med 2009 361 756-65
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OSTEOCLAST REGULATION
PTH
estrogen
1,25 (OH)2D
M-CSF
calcitonin
TRAP
cathepsin K
RANK-L
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CATHEPSIN K INHIBITORS

• odanacatib (Merck)
• 50 mg weekly
• phase 3
• ONO-5334 (Ono)
• 300 mg daily
• phase 2
• MIV-711 (Medivir)
• pre-clinical

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CATHEPSIN K INHIBITORS
odanacatib
ONO-5334
Bone et al. J Bone Miner Res 2010 25 937-47
Eastell et al. J Bone Miner Res 2011 26 1303-12
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CATHEPSIN K INHIBITORS

• similar reduction in bone resorption markers to
  bisphosphonates
• lesser reduction in bone formation markers than
  with bisphosphonates
• rapid offset of action after stopping therapy
• skin adverse events seen with balicatib
• no serious adverse events seen with odanacatib or
  ONO-5334

Boonen et al. Curr Osteoporos Rep 2012 10 73-79
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OSTEOBLAST REGULATION
estrogen
PTH
cortisol
BMP
Wnt/LRP
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OSTEOBLAST REGULATION
estrogen
PTH
cortisol
BMP
dkk
Wnt/LRP
sclerostin
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OSTEOBLAST REGULATION
estrogen
PTH
cortisol
BMP
dkk
Wnt/LRP
sclerostin
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SCLEROSTIN ANTIBODY AMG 785
10 mg/kg SC
5 mg/kg IV
10 mg/kg SC
5 mg/kg IV
Padhi et al. J Bone Miner Res 2011 26 19-26
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FUTURE THERAPIES

• new bisphosphonates
• zoledronate IV infusion annually (safety?)
• oestrogen SERM
• CEE bazedoxifene
• cathepsin K inhibitors
• odanacatib
• antibodies to sclerostin, dickkopf-1
• alternative administration of PTH
• e.g. intranasal spray

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CONCLUSIONS

• various treatment options are available, but all
  carry risks
• HRT remains treatment of choice for prevention in
  women
• new treatments are being developed from our
  better understanding of bone physiology
• targeting cell signalling systems may affect
  tissues other then bone