Medical Treatment for Osteoporosis ~From today to tomorrow

Presented by 劉明村

Miacalcic

Qualitative Effects of SalmonQualitative Effects of SalmonCalcitonin Therapy (QUEST)Calcitonin Therapy (QUEST)

Normal bone Osteoporosis

Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture. Bone strength primarily reflects the integration of bone density and bone quality.

NIH Definition of NIH Definition of OsteoporosisOsteoporosis

NIH Consensus Development Panel on Osteoporosis. JAMA 285 (2001): 785-95

1. Riggs BL et al. N Engl J Med. 1990;322:802–9 2. Ettinger B et al. JAMA. 1999;282:637–453. Chesnut C III et al. Am J Med. 2000;109:267–76

Bone quantity vs bone quality: Evolution of the paradox

35

2–3

1–1.5

3–5

6–8

14

Treatment Increase invertebral BMD (%)

Decrease in vertebralfracture risk (%)

Fluoride1

Raloxifene2

Salmon calcitonin3

Risedronate4

Alendronate5

Strontium-ranelate6

0

30

36

41

47

41

BMD: Bone mineral density

4. Harris ST et al. JAMA. 1999;282:1344–525. Black DM et al. Lancet. 1996;348:1535–416. Meunier P et al. N Engl J Med. 2004;350;459-68

Silva MJ. Gibson LJ. Bone. 1997:21;191–9Parfitt AM. Am J Med. 1991; 91 (Suppl5B):42S-46S.

The importance of architectural integrity

10% decrease in BMD due to loss in trabecular number equals

70% reduction in bone strength

10% decrease in BMD due to loss in trabecular thickness equals

20% reduction in bone strength

Normal bone

Thus, based on BMD alone, anti-

resorptive agents that induce a

greater increase in BMD cannot be

assumed to be more efficacious in

reducing fracture risk than those

producing a lower BMD increase.

ConclusionConclusion

Riggs BL, Melton LJ III. J Bone Miner Res 2002;17:11–4

• 2-year, double-blind, randomized, placebo-controlled study– Miacalcic 200 IU NS vs placebo NS

– All patients received calcium 500 mg daily

• 91 postmenopausal women– At least 5 years post menopause

– 1–5 vertebral fractures at baseline

Study design

Bone turnover – serum CTx

Difference to placebo in serum CTx in the QUEST Study (*p < 0.05)

Ch

an

ge

vs

pla

ceb

o (

%)

QUEST study1 2 years

*

-40

-35

-30

-25

-20

-15

-10

-5

0

1. Chesnut CH III et al. J Bone Miner Res. 2005; in press2. Srivastava A et al. Calcif Tissue Int. 2004;75:477-81

serum CTx

BMD data from QUEST and PROOF

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

Difference to placebo in BMD at the lumbar spine in the QUEST

and PROOF studies at 2 years

Me

dia

n c

ha

ng

e v

s p

lac

eb

o (

%)

QUEST study / 2 years PROOF study / 2 years

1. Chesnut CH III et al. J Bone Miner Res. 2005 in press 2. The Proof study. Data on file

3D visualization from high-resolution MRI

69-year-old male (BV/TV = 0.14)36-year-old male (BV/TV = 0.28)

Beuf O, Ghosh S, Newitt DC et al. Arthritis Rheum 2002;46:385–93

Bone microarchitecture

• Region 1 is 7 mm from the distal endplate

• Regions 1–4 are each 2.5 mm thick (corresponding to 5 MRI slices)

Region 1

Region 2

Region 3

Region 4

MRI of the radiusOnly trabecular structures were evaluated

Radius MRI: Trabecular bone volume

Mean percentage change in apparent trabecular bone volume (BV/TV) from baseline to 24 months

Region 1 Region 2 Region 3 Region 4

p = 0.03 p = 0.01

*

***

***

Miacalcic

Placebo

Change from baseline within group: *p < 0.05; ***p < 0.005

Mea

n %

ch

ang

e

-14

-12

-10

-8

-6

-4

-2

0

2

4

6

-12

-10

-8

-6

-4

-2

0

2

4

6

p = 0.01

p = 0.01

p = 0.05

Region 1 Region 2 Region 3 Region 4

Miacalcic

Placebo

Mean percentage change in apparent trabecular number from baseline to 24 months

**

***

***

Change from baseline within group: **p < 0.01; ***p < 0.005

Radius MRI: Trabecular number

Mea

n %

ch

ang

e

p = 0.01

p = 0.01

Region 1 Region 2 Region 3 Region 4

Miacalcic

Placebo

Mean percentage change in apparent trabecular spacing from baseline to 24 months

*

**

Change from baseline within group: *p < 0.05; **p < 0.01

Radius MRI: Trabecular spacing

**

Mea

n %

ch

ang

e

-6

-4

-2

0

2

4

6

8

10

12

14

16

Bone quality: Microarchitecture

MRI of the hip (trabecular bone)

Four regions of the hip were analysed:

– Ward’s triangle

– Upper trochanter

– Lower trochanter

– Femoral Neck

Hip MRIMean percentage change in T2*, from baseline to 24 months

-6

-4

-2

0

2

4

6

8

10

12

14

Femoral neck

Ward’s triangle

Upper trochanter

Lower trochanter

Change from baseline within group: *p < 0.05; ***p < 0.005

***

*

***

*** Miacalcic

Placebo

Mea

n c

han

ge

fro

m b

asel

ine

(%)

p = 0.049

Conclusions

Treatment with Miacalcic 200 IU NS for 2 years demonstrated

• Improvements (vs. placebo) in bone quality (i.e. BV/TV, trabecular number and spacing) in the forearm (radius), as measured by MRI

• Improvements in bone quality (vs. placebo), expressed by T2 ( decreased 2.6–7.4% relative to placebo) at the hip (femoral neck, Ward’s triangle, upper and lower trochanters), statistically significant at the lower trochanter

• BMD increase of 0.8% (ns) at the lumbar spine vs. placebo

• 26% decrease in bone resorption (p < 0.05), as evaluated by serum CTx

• No differences in the bone formation marker (serum BSAP) compared to placebo

Miacalcic 產品特色

對於治療骨折急性期伴隨骨痛的骨質疏鬆症患者Miacalcic ( 密鈣息 ) 是 :

第一線的快速有效止痛且安全的鼻噴劑藥物 , 它提供增加 β-endorphine 濃度，達到止痛的效果，減少臥床情況。

Miacalcic 長期使用可減少骨質流失 ; 增加骨密度與骨品質 (PROOF and QUEST); 預防再次骨折，增加生活品質。

5.5.2. 抑鈣激素製劑 (Salmon calcitonin nasal spray, injection)

限惡性疾病之高血鈣症或變形性骨炎 (Paget‘s disease)

或停經停經後骨質疏鬆症引起之骨折骨質疏鬆症引起之骨折

健保局給付規範

處方 處方 Miacalcic Miacalcic 之建議之建議

請先了解在處方 Miacalcic 前，是否已完成下列事項： 1. 是否病人已完成骨鬆檢查 (DXA<-2.5DXA<-2.5) ( 需提及為骨質疏鬆症 )

2. 是否詳述病人年齡及性別 ( 需說明停經多久 )

3. 是否有骨折骨折 ( 需附骨折部位之 XX光片光片 )

4. 不得併用 Fosamax , Actonel , Evista , Vitamine D3

5. 是否詳述症狀 - 疼痛嚴重性 , 疼痛多久及部位 , 活動能力6. 請說明病人已經用過同藥理之常用藥品無效，並舉出藥品名稱

藥品代碼 藥品名稱 價格 劑型

B015478255 MIACALCIC AMPOULES 100I.U./ML 361.0 注射劑B016704248 MIACALCIC INJECTION 50 MRC-U/ML (50IU /ML) 201.0 注射劑B022448415 MIACALCIC NASAL SPRAY 200I.U. 2.8KIU/BOT 14PUFF 1,976.0 鼻用氣化噴霧

Zoledronic Acid:Annual Bone Health management for Osteoporosis

~ From Cancer treatment to Paget’s Disease and PMO treatment ~

Molecular Structure of Zoledronic Acid

– Zoledronic acid is a potent nitrogen–containing bisphosphonate

Green JR, et al. J Bone Miner Res. 1994;9:745-751.

NNNN

PP

OO

OO

PP

OHOH

OHOH

OHOH

OHOHHOHO

CC

• Core bisphosphonate moiety (red arrows) Core bisphosphonate moiety (red arrows) • Core bisphosphonate moiety (red arrows) Core bisphosphonate moiety (red arrows)

• RR22 side chain: imidazole ring (blue arrows) side chain: imidazole ring (blue arrows) • RR22 side chain: imidazole ring (blue arrows) side chain: imidazole ring (blue arrows)

BP BPBP

High-affinity BPs may diffuse less well in bone and remain nearer accessible surfaces

High re-attachment through recycling

BP

Low desorptionBP

Avid uptake

G Russell (2005).

Zoledronic acid has high affinity for Zoledronic acid has high affinity for bone mineral leading to:bone mineral leading to:

Zoledronic acid has high affinity for Zoledronic acid has high affinity for bone mineral leading to:bone mineral leading to:

HO

NN

O

O

=

=

P

P

OHOH

OHOH

ZOL has long duration of action

Proposed Mechanism of Local Recycling of Zoledronic Acid in Bone

1. Nancollas GH, et al. Bone. 2006, in press. 2. Dunford JE, et al. J Pharmacol Exp Ther. 2001;296:235-242.

Binding to HydroxyapatiteBinding to Hydroxyapatite11Binding to HydroxyapatiteBinding to Hydroxyapatite11

0

1

2

4

3

KL

(L/m

ol x 1

06)

CLO ETD RIS IBA ALN ZOL

ALN IBA RIS ZOL

IC5

0 (

mM

)0.0

0.1

0.2

0.3

0.4

0.5rhFPP synthaserhFPP synthase22rhFPP synthaserhFPP synthase22

Zoledronic Acid: Key Pharmacological Characteristics

• High binding affinity for bone in vitro– Maximizes attachment

– Minimizes detachment

• Potent FPP synthase inhibition in vitro– Maximizes antiresorptive

potential

– Minimizes total amount of drug required

– Allows single administration of total annual dose

Pharmacological Properties of Zoledronic Acid

– Achieves prolonged suppression of bone resorption

– No deleterious effect on bone quality

– Increases bone mineral density

– Reduces bone turnover

– Does not impair mineralization

– Has favourable effects on structural & mechanical properties of bone

– IV administration does not blunt bone anabolic response to PTH

Zoledronic Acid Demonstrated Broad Efficacy in Women With Postmenopausal Osteoporosis• In women with postmenopausal osteoporosis, once yearly infusion

of ZOL 5 mg over 3 years significantly reduces1:– Vertebral fractures (morphometric 70%, clinical 77%)1

– Hip fractures (41%)1

– Non-vertebral fractures (25%)1

– Days of disability due to fracture or back pain2

– Height loss1

• Significantly superior to placebo in increasing or preserving BMD1

• Markers of bone formation and resorption were reduced and maintained within premenopausal reference range over 36 months1

• Generally well tolerated1

• Fracture efficacy coupled with high adherence suggests potential role for ZOL 5 mg as treatment for osteoporosis1

1. Black DM, et al. N Engl J Med. 2007;356:1809-1822. 2. Black DM, et al. Presented at: ASBMR 28th Annual Meeting; September 15-19, 2006;

Philadelphia, Pa. Abstract 1054.(n=7,736)

The HORIZON Recurrent Fracture Trial

*Lyles KW, et al. N Engl J Med. 2007;10.1066:1-11.

Recurrent Fracture Trial Study Conclusions

Zoledronic acid*: significantly reduced risk of overall clinical fracture by 35% and multiple

clinical fractures by 33%

significantly reduced mortality risk by 28%

significantly reduced risk of clinical vertebral and non-vertebral fractures by 46% and 27%, respectively

had a 30% lower risk in hip fractures compared to placebo (NS)

significantly increased/preserved total hip and femoral neck BMD at all time points

showed comparable incidence of AEs and SAEs to placebo

demonstrated no evidence of long-term effect on renal function

demonstrated a 20% reduction in risk of atrial fibrillation/atrial flutter SAEs (n=12, 1.1%) relative to the placebo (n=15, 1.4%)

No adverse effects on fx. healing or ONJ risk(n=2,127; men and women)

*Lyles KW, et al. N Engl J Med. 2007;10.1066:1-11.

Zoledronic Acid will Improve Patient Compliance as Once-Yearly IV Therapy is Preferred

Data from Lindsay R, et al. Poster presented at ECCEO6; March 15-18, 2006; Vienna, Austria.

16.4

18.9

Both Are EqualOnce-Yearly IV

Once-Weekly Pill

More convenient

More willing to take long term

Overall preference

N = 122

66.4

59.8

0 20 40 60 80 100

68.0

66.4

15.618.0

20.5

15.6

19.713.9

% of Patients

More satisfying

Thanks for your attention!Thanks for your attention!

Aclasta is coming soon……