advances in osteoporosis treatment john c stevenson national heart & lung institute imperial...
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Advances in osteoporosis treatment
John C StevensonNational Heart & Lung Institute
Imperial College London
Royal Brompton Hospital
London, UK
PREVENTION & TREATMENT
• HRT
• tibolone
• SERMs
• bisphosphonates
• strontium
• calcitonin
• teriparatide• ? strontium• ? HRT
anti-resorptive bone formation
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
• 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: 826-31Seghizadeh et al. J Am Dent Assoc 2009; 140: 61-66Sharma et al. N Engl J Med 2008; 359: 1410-11
Green et al. BMJ 2010; 341: c4444Schilcher et al. N Engl J Med 2011; 364: 1728-37
NEW TREATMENT APPROACHES
• target signalling systems to bone cells
• target cellular action of bone cells
OSTEOCLAST REGULATION
TRAP cathepsin KRANK-L
M-CSF
PTH
1,25 (OH)2Destrogen
calcitonin
OSTEOCLAST REGULATION
TRAP cathepsin KRANK-L
M-CSF
PTH
1,25 (OH)2Destrogen
calcitonin
DENOSUMAB AND FRACTURES
• 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) 0
2
4
6
8
10
vertebral hip
% in
cide
nt f
ract
ures
p<0.001
Cummings et al. N Engl J Med 2009; 361: 756-65
denosumab
placebo
p<0.05
OSTEOCLAST REGULATION
TRAP cathepsin KRANK-L
M-CSF
PTH
1,25 (OH)2Destrogen
calcitonin
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 INHIBITORS
0
1
2
3
4
5
6
spine hip
% B
MD
cha
nge
over
2 y
ears
0
1
2
3
4
5
6
spine hip
% B
MD
cha
nge
over
2 y
ears
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 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
PTH
Wnt/LRP
BMP
estrogen
cortisol
OSTEOBLAST REGULATION
PTH
Wnt/LRP
BMP
estrogen
dkk
sclerostin
cortisol
OSTEOBLAST REGULATION
PTH
Wnt/LRP
BMP
estrogen
dkk
sclerostin
cortisol
SCLEROSTIN ANTIBODY AMG 785
-100
-50
0
50
100
150
200
% c
hang
e
P1NP BALPostecalcin CTX
0
1
2
3
4
5
6
% B
MD
cha
nge
spine hip
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
• 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
• 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