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Advances in osteoporosis treatment. John C Stevenson National Heart & Lung Institute Imperial College London Royal Brompton Hospital London, UK. PREVENTION & TREATMENT. anti-resorptive. bone formation. HRT tibolone SERMs bisphosphonates strontium calcitonin. teriparatide

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advances in osteoporosis treatment

Advances in osteoporosis treatment

John C Stevenson

National Heart & Lung Institute

Imperial College London

Royal Brompton Hospital

London, UK

prevention treatment
PREVENTION & TREATMENT

anti-resorptive

bone formation

  • HRT
  • tibolone
  • SERMs
  • bisphosphonates
  • strontium
  • calcitonin
  • teriparatide
  • ? strontium
  • ? HRT
hrt risks
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

bisphosphonates risks
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 >3 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

new treatment approaches
NEW TREATMENT APPROACHES
  • target signalling systems to bone cells
  • target cellular action of bone cells
osteoclast regulation
OSTEOCLAST REGULATION

PTH

estrogen

1,25 (OH)2D

M-CSF

calcitonin

TRAP

cathepsin K

RANK-L

osteoclast regulation1
OSTEOCLAST REGULATION

PTH

estrogen

1,25 (OH)2D

M-CSF

calcitonin

TRAP

cathepsin K

RANK-L

denosumab and fractures
DENOSUMAB AND FRACTURES

denosumab

  • 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)

placebo

p<0.001

p<0.05

Cummings et al. N Engl J Med 2009; 361: 756-65

osteoclast regulation2
OSTEOCLAST REGULATION

PTH

estrogen

1,25 (OH)2D

M-CSF

calcitonin

TRAP

cathepsin K

RANK-L

cathepsin k inhibitors
CATHEPSIN K INHIBITORS
  • odanacatib (Merck)
    • 50 mg weekly
    • phase 3
  • ONO-5334 (Ono)
    • 300 mg daily
    • phase 2
  • MIV-711 (Medivir)
    • pre-clinical
cathepsin k inhibitors1
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

cathepsin k inhibitors2
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

osteoblast regulation
OSTEOBLAST REGULATION

estrogen

PTH

cortisol

BMP

Wnt/LRP

osteoblast regulation1
OSTEOBLAST REGULATION

estrogen

PTH

cortisol

BMP

dkk

Wnt/LRP

sclerostin

osteoblast regulation2
OSTEOBLAST REGULATION

estrogen

PTH

cortisol

BMP

dkk

Wnt/LRP

sclerostin

sclerostin antibody amg 785
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

future therapies
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
conclusions
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
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