골다공증치료의최신지견 · 2010. 3. 29. · TOP (Treatment of Osteoporosis with...

2010 대한가정의학회 춘계학술대회

골다공증 치료의 최신지견

제일병원가정의학과

오한진


3년 PDL 치료 후

스테로이드 사용 후 골절 사례


PTH= Parathyroid Hormone

새로운 골다공증 치료약제


Bone remodeling and drug targets

Canalis et al. NEJM 2007:357:905

Anti-resorptive

Anabolic


70% increase

Untreated Baseline After hPTH(1-34) Treatment

hPTH(1-34) increases Trabecular Bone Volume

Reeve, Meunier, et al. BMJ 1980;280:1340-1344

Action of rPTH


Once-daily Continuous

RANKL OPG

Osteoclast

bone resorption

serum Ca++

Osteoblastapoptosis

boneliningcells

cbfa1 BMP Wnt IGF1,2 Amphiregulin OPG RANKL

Osteoblast number/function

bone formation

bone mass/strength

PTH action Mechanism


Mechanisms of PTH anabolism

Effects on cells Increase development of OB

Inhibit osteoblasts apoptosis

Reactivate lining cells

Attenuation of adipogenesis

Auto/paracrine regulators IGF-I/FGF-2

Sclerostin and Wnt signaling

RANKL/OPG

Jilka et al. Bone 40:1434-46, 2007


Anabolic window

Period of OB Stimulation

Period ofRemodeling activation


Homeostatic role:

Sustained elevation of PTH

maintain s-Ca

by withdrawal from bone ‘bank’

reduces bone mass.

Therapeutic role:

Short pulses of PTH

build bone mass.Continuous PTH

(>2 hrs/day):bone massIntermittent PTH

(


Changes in BMD

BMD Change Placebo PTH 20 mg PTH 40 mg

L-spine ( Δ%) 1.1 9.7* 13.7*

F. neck ( Δ %) - 0.7 2.8* 5.1*

Total hip ( Δ %) - 1.0 2.6* 3.6*

Radial shaft

( Δ %)- 1.3 - 2.1 - 3.2*

Neer et al., N Engl J Med 344:1434, 2001


Undermineralized new bone BMD

Cortical porosity

Increased diameter & thickness

Fracture

PTH

Cortical bone change


Effects of Continuous vs. Intermittent hPTH(1-34) on Osteoblasts and Osteoclasts in Male Rats

*P


FACT TrialL-Spine BMD; Areal (DXA) and Volumetric (QCT)

McClung, et al. J Bone Miner Res 2003:18(Suppl 2):S40

*P


FACT Study: Bone Markers

NTx = bone resorption

PINP = bone formation

TPTD - Bone Formation Resorption Markers

Months

0 1 3 6 12

Me

an

% c

han

ge

with S

E

-100

-50

0

50

100

150

200

250

NTx

PINP

TeriparatideALN - bone formation and resorption markers

Months

0 1 3 6 12

Me

an

% c

ha

ng

e w

ith

SE

-100

-50

0

50

100

150

200

250

NTx

PINP

*

Alendronate

% Change from baseline (Mean SE)

McClung M et al. Arch Int Med 2005; 165:1762-1768Arlot M, Meunier P et al. JBMR, 2005;20:1244-53

P


Teriparatide Improves Skeletal Architecture

Baseline Follow-up

Patient treated with teriparatide 20µg

Jiang et al., J Bone Min

Res 2003;18(11):1932-1941

Female, age 65

Duration of therapy: 637 days (approx 21 months)

BMD Change:

Lumbar Spine: +7.4% (group mean = 9.7 ± 7.4%)Total Hip: +5.2% (group mean = 2.6 ± 4.9%)


Importance of Connectivity:REVERSING Osteoporosis

Healthy HumanIliac Crest Biopsy

Osteoporotic HumanIliac Crest Biopsy

Osteoporosis

PTH


hPTH(1-34)+ET vs ETin Postmenopausal Women with Osteoporosis

Sustained Increase in Spine BMD over 3 Years

Spine BMD

Months of treatment

0 6 12 18 24 30 36

% change from

baseline

-5

0

5

10

15

PTH+ET

ET

Total Hip BMD

Months of treatment

0 6 12 18 24 30 36

% c

hange from

baseline

-5

0

5

10

15

PTH+ET

ET

†

†

†

††

†

**

Lumbar Spine BMD Total Hip BMD

PTH + ET

ET

Lindsay et al. Lancet 1997;350:550-555

†P


0

2

4

6

8

10

12

14

placebo TPTD20 TPTD40

Risk Reduction in Vert. & Non-Vert. Fx

0

1

2

3

4

5

6

7

placebo TPTD20 TPTD40

Neer et al., N Engl J Med 344:1434, 2001

Vertebral Fx Non-vertebral Fx


Effect of Teriparatide on the Risk of Moderate or Severe New Vertebral Fractures

Neer et al. N Engl J Med 2001; 344(19):1434-1441

Moderate or Severe Fractures

% o

f w

om

en w

ith

>1 m

oderate

or s

evere fractu

re

0

2

4

6

8

10

Placebo(42 / 448)

TPTD20(4 / 444)

TPTD40(9 / 434)

*P 1 m

odera

te o

r se

vere

fra

ctu

re

RR 90%*ARR = 8.47% RR 78%*

ARR = 7.30%

3

3

Severe

fracture

Severe

fracture


Reduced riskNew vert. Fx 65-69%Mod. severe vert. fx 90%Non-vert. fragility fx. 53-54%

Increased BMD Spine 10-14%Femoral neck BMD 3-5%

Reduced New/worsening back pain Fracture-associated height loss

Fracture Prevention TrialSummary of Once-daily Teriparatide

Neer et al. N Engl J Med 2001; 344(19):1434-1441


TPTD Trial in MenEffects on Lumbar Spine BMD

Months

0 3 6 12

Mea

n %

cha

nge

from

bas

elin

e

0

2

4

6

8

10

12

*

*

*

*

*

*

Placebo TPTD20 TPTD40

Mean %

change f

rom

base

line ±

SE

*P


Teriparatide Trial in Men; Effects on Hip BMD

Orwoll, et al. J Bone Miner Res 2003; 18(1):9-17

Mean %

change f

rom

base

line

SE

Femoral Neck - BMD - GHAJ

Me

an

% c

ha

ng

e fro

m b

ase

lin

e ?

SE

0

1

2

3

4

TPTD40

*

2.93

1.53

0.31

*P


Months0 3 6 9 12 15 18

0.0

0.02

0.04

0.06

0.08

0.10

0.12

Ch

an

ge in

sp

ine B

MD

(g

/cm

²)

Women

Men

TPTD20

Satterwhite et al. Arthritis and Rheum 2001:44(9)(Suppl):S255Data on file – Eli Lilly and Company

Teriparatide Trial ; Effects on spinal BMD


Teriparatide Trial in Men; Summary

In men with osteoporosis

BMD ;

similar in magnitude with women

Increased spine & femoral BMD

Increased total body BMC


PTH + Antiresorptive Therapy

- PTH + Bisphosphonate

- PTH + Raloxifene

- PTH + HRT

Teripartide After Antiresorptive

After Teripartide withdrawal

Combination & sequential therapy


Black DM et al. N Engl J Med

2003;349:1207-1215.

The effects of parathyroid hormone

and alendronate alone or in

combination in postmenopausal

osteoporosis

Combination Therapy; PTH + ALN


Black DM et al. N Engl J Med 2003;349:1207-1215.



No evidence of synergy between PTH and ALNCombination Therapy; PTH + ALN


Finkelstein JS, N Engl J Med. 2003;349(13):1216-26

Effects of PTH, Alendronate, or Both in Men


Finkelstein JS, N Engl J Med. 2003;349(13):1216-26



% Changes of BMD According to TreatmentBlack DM, et al. N Eng J Med 2005;353: 555-565


Mean % Changes in Volumetric BMD & Cortical Measurements Derived from Quantitative CT

Black DM, et al. N Eng J Med 2005;353: 555-565

BMD in trabecular bone at spine BMC in trabecular bone at hip

BMD in cortical bone at hip BMC in cortical bone at hip


Geometric % Changes in Bone Markers

Black DM, et al. N Eng J Med 2005;353: 555-565


RLX

ALNRLX

ALN

*10.2

$4.1 $1.8

0.3

Ettinger B. et al. J Bone Miner Res 2004;19:745-51.

% BMD change by previous Tx. with RLX or ALN

Total hipLumbar spine


Bone markers by previous Tx with RLX or ALN

Osteocalcin Bone ALP

RLX RLX

ALN

ALN

Ettinger B. et al. J Bone Miner Res 2004;19:745-51.


L-spine BMD changes during & after treat. with rPTH Lindsay R, et al, Arch Intern Med. 2004;164:2024-30.

18mo

No drug use Bisphosphonate use

P


Hip-BMD changes ; Fracture Prevention Trial.

Prince R, et al, J Bone Miner Res 2005:20:1507-13

*p < 0.001

No drug use Bisphosphonate use

30-Mo


FN-BMD changes ; Fracture Prevention Trial.Prince R, et al, J Bone Miner Res 2005:20:1507-13

Bisphosphonate useNo drug use

*p < 0.001


Summary :Combined/Sequential Tx with rPTH

Combined therapy with Teriparatide

- Ca and Vit. D if intake is inadequate

- Tx with HT & Raloxifene is possible

- Combine with BPs is not recommended

Sequential Treatment

- No rationale for a drug ‘holiday’

before starting teripartide

- An antiresorptive agents after PTH

(raloxifene or bisphophonate)

to maintain the benefit


TOP (Treatment of Osteoporosis with Parathyroid hormone) trial

2,532 postmenopausal women

45-54 yrs

T


Fracture outcome with PTH (1-84)

58%

68%

No pre-existing VF

53%

pre-existing VFVF % VF %

Ann Intern Med 2007;146:326

0

1

2

3

4

5

6

7

8

9

PTH(1-84) placebo0

0.5

1

1.5

2

2.5

PTH(1-84) placebo


BMD changes with PTH(1-84)

6.9%

2.1%

2.5%

3.4%



Bone markers with PTH(1-84)


PTH

Placebo

PTH

Placebo


Commercial Products

PTH(1-34): teriparatide, FORTEO®

PTH(1-84): Preotact™, PREOS® (EU)

Recommended dosage

20 mcg [1-34]

100 mcg[1-84] once a day

Up to 2 yrs in US, 1.5 yrs in EU & Korea

Candidate type

oral, intranasal, transdermal type


Warnings

Increased risk of osteosarcoma, not be treated with rPTH Paget’s disease of bone unexplained elevations of alkaline

phosphatase Pediatric populations Prior external beam implant radiation involving the skeleton

Patients ; following conditions should not receive rPTH Bone metastases History of skeletal malignancies Metabolic bone dis. other than osteoporosis Pre-existing hypercalcemia Pregnancy or lactation


Teriparatide

Side Effects- nausea and

orthostatic hypotension

- transient and asymptomatic hypercalcemia

- muscle pain- Headache- HTN, angina- osteosarcoma

in animal

Contraindications

- Paget’s disease- history of irradiation

involving the skeleton- skeletal malignancy- pregnancy - lactation


Summary of PTH

PTH

only one, approved anabolic agent

Effective

decrease vert. & nonvert. fx

Effective

postmenopausal, male & GIO

Combine and sequential therapy

No consensus for a drug ‘holiday’

before starting PTH

Sequential Antiresorptives

to maintain benefit after PTH


Summary of PTH

Multiple actionPotential to reconstruct the skeletonPx. of vertebral & nonvertebral FxUse within 2 years(18-Mo)Use in severe osteoporosis- Osteoporotic fractures- With very low T-score- Can’t tolerate BPs- Fx. while on antiresorptive therapyCombination with bisphosphonates not recommended

Maintain the benefit (BMD gain) antiresorptive agnts use after PTH (raloxifene or bisphophonate)


Therapeutic Management

Raloxifene

At RiskOsteopenia Osteoporosis

SevereOsteoporosis

LowerHigher

T-Score: -2.5

BMD

Calcitonin

ET/EPT

After Vasomotor Symptoms

Before fracture After Fracture

AGE

PTH

BisphosphonatesDenosumabCathepsin K inhibitor

Strontium ranelate

During

Hot Flashes


Strontium

-Ranelate

새로운 골다공증 치료약제


Strontium Ranelate


Strontium

1950s; Firstly use ; osteoporosis Tx

Do not exist free form

Because of oxidate tendency

Source: vegetables and cereals

25-30%

absorbed by the jejunum

Vit D, lactose, carbohydrate

Calcium, phosphorous

Renal clearance

3 ; 1 (Sr ; Ca)

Tubular reabsorption is lower (< Ca)


Strontium Ranelate: Dual Mode of Action

Dual mode of action

Stimulates bone formation

Decreases bone resorption

In animal studies

Prevent bone loss in OVX rats

bone mass in osteopenic animals

bone strength in normal animals

No deleterious effects on mineralization


Osteoclastapoptosis

Summary of Action Mechanism


Clinical Trials of SR

STRATPS(Strontium Ranelate for Treat. of Osteoporosis)

PREVOS

Prx. of Early postmenopausal bone loss

by Strontium Ranelate

STRATOS

Strontium Administrate for Tx of Osteoporosis)

SOTI

Spinal Osteoporosis Therapeutic Intervention

TROPOS

Treatment of peripheral Osteoporosis

Lam S. Consult Pharm 2008 23; 531-7


Clinical Trials of SR

STRATPS conclusion

4 clinical trials demonstrate Efficacy

Safety of Strontium Ranelate

For management of PMO

FDA

Not approved for that indication


Spinal Osteoporosis Therapeutic Intervention (SOTI)

DB-RCT, 1,649 PMW, 3-year study

with osteoporosis (low BMD)

at least 1 vertebral fracture,

Strontium ranelate (2g/day) vs. PCB

Primary outcome:

vertebral fractures

BMD

http://content.nejm.org/


49%

41%At 12 months: 0.51 (95% CI: 0.36-0.75; P


BMD at the L-Spine and Femur

Adjusted for the Sr content

Bone strontium content defined

bone biopsy samples

obtained at 36-Month

L-Spine BMD was calculated

Adjustment factor

= 1 ÷ [1+(Bone Sr content x 0.61)]


Change in Vertebral BMD

12.7%6.8% After adjust

-1.3%

Difference: 8.1%Comparable PTH(20 μg) for 21 Mo


Changes in Hip BMD

Femur Neck

Total Hip


Changes in Bone Markers

Bone Specific Alk- P C-Telopeptide


Changes in Bone Markers

Dissociation between reduced bone resorption and

increased bone formation


Histomorphometric Features & s-Strontium Conc.

No evidence of osteomalacia

Or primary mineralization defect

No increase in osteoid thickness

Or mineralization lag time

No decrease in mineral apposition rate

Strontium in bone correlate with plasma

At baseline,

median s-Sr conc.: 0.3 μmol/L

At 3 months,

median s-Sr conc.: 117.9 μmol/L

reached a plateau


Adverse Events

Most frequent AE; Diarrhea (6.1%)

disappears after first 3 months

S-Ca were lower & s-phosphate higher

Sr group at 3-Mo, with a plateau

Slight reduction s-PTH

6-Mo in both groups,

more reduction in Sr group

S-CK (MM) increased in some patients,

no increase in muscular symptoms

No other biologic abnormalities

transient, returned normal during tx


Assess efficacy and safety

in preventing non-vertebral fracture

DB-RCT, 5,091 PMO, 5-year study

Strontium ranelate (2g/day)

vs. placebo


Primary outcome:

non-vertebral fractures,

major fragility fractures

(hip, wrist, pelvis and sacrum,

ribs, sternum, clavicle, humerus)

Sub-analysis:

Hip fractures (1,977)

at high risk of hip fracture

(age≥74 yrs & FN BMD≤-3.0)

Vertebral fractures (3,640)

yearly vertebral X-rays

TROPOS Study


Study Design

FIRST (Fracture International Run-in SR Trial):Normalize subject’s Ca and Vit- D status


Study Subjects

75 centers

in 11 European countries

in Australia

Inclusion criteria

FN BMD 0.600 g/cm2,

Same as T-score < -2.5

74 year or older

Aged between 70-74 year

With 1-additional frx. risk


Baseline Characteristics


New Fractures for the ITT Population

16%

19%

34%


Femoral Neck BMD

5.7%

Combined effects: • Strontium distribution in bone• Strontium increased x-ray absorption• Strontium may account for approx. 50%of the measured changes in BMD

8.2%


Adverse Effects

Well tolerate

strontium group: first 3 months

nausea (7.2%), diarrhea (6.7%)

headache (5.5%)

dermatitis and eczema (5.5%)

Small changes :

decrease in Ca and PTH,

increase in phosphate:

activation of CaR,

not aw clinical consequence


To determine

Effective in osteopenia

Data from the SOTI & TROPOS (3 year)

Women Spinal osteopenia (1,166)

Women osteopenia at both sites (265)


Reduction of Verte. Frx. Risk in Osteopenia


Vert. Fx Risk in Osteopenia at LS and FN


Vertebral Fx Risk Reduc. in Various Conditions


1,488 women

between 80 & 100 yrs of age(of SOTI and TROPOS)


Vertebral/Non-vertebral Frac. in the Elderly

Vertebral Fracture Non-vertebral Fracture


Hip/Clinical Fracture Risk in the Elderly

Hip Fracture Clinical Fracture


Anti-fracture Efficacy of SR

Over 5 yrs, data were available in 4935 patients for ITT analysis (Reginster JY, et al. Effects of long-term strontium ranelate treatment on the risk of non-vertebral and vertebral fractures in post menopausal osteoporosis: results of a 5-year, randomized, placebo-controlled trial. Arthritis Rheum. 2008 Jun;58(6):1687-95)


Fracture Efficacy of SR

SR safely reduces

risk of vert. and non-vert. Fx

In PMW over 50

In women over 80 yrs

with & without a prevalent Fx

In women with osteopenia

Risk reduction ;

within 6-12 Mo of Tx

Effect is sustained for 5 years


Strontoum Ranelate

1. Enhances

pre-OB replication,

OB differentiation,

collagen synthesis

matrix mineralization

2. Decreases RANKL, increases OPG

3. Decrease

OC differentiation, activity

promote apoptosis

4. Enhances

bone structure and biomechanics


Strontoum Ranelate

Overall effect

rebalanced bone turnoverimproved bone geometry, cortical thickness, trabecular bone morphology intrinsic bone tissue quality

enhanced bone strength


Strontium Ranelate

SR was deposited

dose-dependent manner

Bone SR content ; plateau 2-3 yrs of tx.

SR was absorbed

onto the mineral surface

rather than substituting for Ca ion,

rapid clearance of SR on bone

True BMD increase is difficult to interpret,

higher atomic number (38 vs. 20),

weaken x-ray penetration

BMD is overestimated by approx. 50%


One 2-g sachet once daily by mouth

mixed in a glass of water

taken at bed-time or between meals

(at least 2 hours after eating):

absorption is reduced by food, milk, Ca

No dosage adjustment

relation to age

mild to moderate renal impairment

Not recommend in severe renal impairment (CCr < 30mL/min)

Protos®


Use with Caution in

Severe renal impairment

History of VTE (DVT, PE)

Blood disorders

increase risk of blood clots

anti-phospholipid syndrome,

factor V Leiden

Phenylketouria

Protos contain aspartame, ; source of phenylalanine


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골다공증치료의최신지견 · 2010. 3. 29. · TOP (Treatment of Osteoporosis with...

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