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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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