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