비스포스포네이트 장기 치료의

효과와 안정성

서울아산병원 내분비내과

고 정 민

골다공증 치료제

• 칼슘 , 비타민 D

• 골흡수 억제제 : 에스트로겐

선택적 에스트로겐 수용체 변형체

비스포스포네이트

칼시토닌

• 골형성 촉진제 : Teriparatide (PTH1-34)

• 스트론튬 (Strontium Ranelate)

치료 제 비교 : 골절 감소 효과

약제 연구명 ( 기간 ) 척추 비척추 고관절

에스트로겐 WHI (5.2 년 ) -34% -23% -34%

알렌드로네이트 FIT (3 년 ) -55% - -51%

리제드로네이트 VERT (3 년 ) -41% -39% -40%

랄록시펜 MORE (4 년 ) -30 ~ -55% NS NS

칼시토닌 PROOF (5 년 ) -36% NS NS

테리파라타이드 FPT (2.1 년 ) -65% -53% -

스트론튬 라닐레이트 STRATOS (3 년 ) -41% -19% NS

비스포스포네이트 제재

O

O- P O-

R1 C R2

O- P O-

O

세대 약제 효능

1 Etidronate 1

Clodronate 10

2 Tiludronate 10

Pamidronate 100

Alendronate 100-1000

3 Risedronate 1000-10000

Ibandronate 1000-10000

Zoledronate 10000

결합력

효능

대사 및 분포

• 경구 투여 시 생체 이용률 : 0.9 ~ 1.8%

• 생체 내 대사가 없음

• 약제 분포 :

뼈에 특이적으로 결합 ( 흡수된 양의 40 ~ 60%)

• 제거 : 1. 소변으로 제거

2. 골 교체가 일어날 때 뼈로부터 제거

• 약제를 투여하여 제거할 방법이 없다 .

Pharmacokinetics

• Very little accumulation in bone

For 10 yrs, total 75 mg in whole skeleton

• After stopping, 6 g/day release

• After stopping, suppressed bone turnover for at least 5 yrs.

Alendronate 20 mgAlendronate 5 mgPlacebo

기 전

Another Mechanisms

• 조골세포 표면의 RANKL 감소

파골세포 형성 억제

• 조골세포로의 분화 촉진

• 조골세포와 osteocyte 의 세포자멸사 억제

• 역할 : 1) 복구 기전 : 새로운 뼈로 교체 골력의 유지

2) 칼슘 항상성

• High bone turnover rate in post-menopause

- 3 times for pre-menopause

- New bone remodeling before full mineralization

- Decreased BMD & deterioration of bone microarchitecture

골재형성 (Bone Remodeling)

Reduction of Fracture by Antiresorptives

• Suppression of increase in bone resorption

• Increased bone mass

- Time differences between resorption & formation

- Secondary mineralization

Resorption vs. Fracture Reduction

• Not closely linked to the increase in bone density

• No proven effects of combination of resorptive agents f

or fracture reduction

• Risedronate hip study (McClung et al. N Engl J Med, 333)

- 5.0 mg/day vs. 2.5 mg/day

- Further increased BMD & decreased bone turnover

- No further reduced fracture risk

Physiological Physiological RRangeange

Bo

ne

Str

en

gth

Bone Turnover

Excessive turnover• Increase in stress risers (weak zones)• Increase in perforations• Loss of connectivity

Insufficient turnover• Accumulation of microdamage• Increased brittleness due to

excessive mineralization

Optimal Reduction of Bone Turnover

Adequacy of

Suppressed bone resorption

By bisphosphonates?

Reduction Bone Turnover

Raloxifene

RisedronateAlendronateZoledronate

Risedronate Alendronate

Preclinical Animal Studies

• Marked reduction in

bone turnover

• Increased bone

volume and density

• Doubling of

mechanical strength

• Fracture healing was

not impeded

In Human … Using bone biopsy,

With usual doses of the bisphosphonates

Suppression of bone-forming surface by 60-90%

Hypermineralization?

How long

Suppressed bone resorption

By bisphosphonates?

No Accumulation of Bone Turnover

Urinary NTx BSAP

Slight Gain of BMD 10 Years

FIT ALN for 5 years PBO (N=437) ALN 10mg (N=333) ALN 5 mg (N=329)

Clinical spinal fractures RR 0.45 [0.23-0.84]

Non-spine fractures RR 1.00 [0.76-1.32]

Morphometric fracture RR 0.87 [0.61-1.25]

Number of Fractures in 10 yrs (FLEX)

Delayed/Absent Fracture HealingDuration ofALN Tx (yr)

OtherMedications

Delayed/absenethealing on ALN

Fracture healing(months off ALN)

6 - NA No (12)

7 - NA Yes (6)

8 - 4 m No (9)

8 - NA No (9)

3 E2 3 m Yes (8)

5 E2 2 yr Yes (4)

5 E2 9 m Yes (5)

3 Prednosolone 2 yr No (8)

4 Prednosolone 8 m Yes (3)

Bishphosphonate therapy in osteoporotic patients should be stopped after

5 years, pending additional research

Normal

PatientsNormal

OCOsteoid

OB

Patients

• ….it seems reasonable to suggest discontinuation for some indefinite period of time after 5 years of use in younger lower-risk postmenopausal women.

Miller PD Expert Opin Pharmacother 2003 4:2253

• … bisphosphonate therapy in osteoporotic patients should be stopped after 5 years, pending additional research

Ott SM J Clin Endocrinol Metab 2005 90:1897

Osteonecrosis of the Jaw (ONJ)• No universally accepted definition

of ONJ

• Typically appears as an area of

exposed alveolar bone that can

occur in the mandible or maxilla.

• It may or may not be painful.

• It may or may not be associated with infection or local

trauma.

• First report: 2003

• In many, occurrence after recent dental pathology, trauma,

or oral surgery.

Osteonecrosis• Most were treated with IV bisphosphonate

had very poor oral health

had serious comorbidities such as cancer

• Much smaller number of cases

of ONJ have been associated

with oral bisphosphonates used

at lower doses to treat

osteoporosis / Paget’s disease.

• Millions of osteoporosis patients are estimated to

have taken oral bisphosphonates.

Prostate Ca.5%

Other6%

MM44%

Osteoporosis13%

Breast Ca32%

Figure 1. Time to the Onset of Osteonecrosis of the Jaw in Patients with Myeloma Receiving Zoledronic Acid or Pamidronate.

Durie et al., N Engl J Med 353:99, 2005

Osteonecrosis

• Many also had a medication history, such as

chemotherapy or corticosteroids.

• No ONJ in RCT for osteoporosis

- > 60,000 patient-years of exposure

- Recently, ON of external auditory canal

• By Council on Scientific Affairs of the American Dental

Association

- 170 ONJ with ALN, and 20 with RISE

• ASBMR Task Force Team on ONJ …

Recommendations for ONJ

Conclusions• Short-term reduction of bone turnover: no problem

• Low risk of long-term reduction of bone turnover, such as brittle

bone and ONJ

• No proven effects of additional 5 year treatment for

fracture reduction

• Although it was very low, possible risk for delayed fracture

healing or ONJ

- Long-term medications (> 5 years?)

- According to co-morbidities or co-medications

• Five years treatment Switch with another drugs, or

skipping?