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비스포스포네이트 장기 치료의 효과와 안정성

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.

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비스포스포네이트 장기 치료의 효과와 안정성

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  1. 비스포스포네이트 장기 치료의 효과와 안정성 서울아산병원 내분비내과 고 정 민

  2. 골다공증 치료제 • 칼슘, 비타민 D • 골흡수 억제제: 에스트로겐 • 선택적 에스트로겐 수용체 변형체 • 비스포스포네이트 • 칼시토닌 • 골형성 촉진제: Teriparatide (PTH1-34) • 스트론튬 (Strontium Ranelate)

  3. 치료 제 비교: 골절 감소 효과

  4. 비스포스포네이트 제재 결합력 O O-P O- R1 C R2 O-P O- O 효능

  5. 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.

  6. Alendronate 20 mg Alendronate 5 mg Placebo 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.

  7. 기 전

  8. Another Mechanisms • 조골세포 표면의 RANKL 감소 •  파골세포 형성 억제 • 조골세포로의 분화 촉진 • 조골세포와 osteocyte의 세포자멸사 억제

  9. 골재형성 (Bone Remodeling) • 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

  10. Reduction of Fracture by Antiresorptives • Suppression of increase in bone resorption • Increased bone mass • - Time differences between resorption & formation • - Secondary mineralization

  11. Resorption vs. Fracture Reduction • Not closely linked to the increase in bone density • No proven effects of combination of resorptive agents for 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

  12. Physiological Range Optimal Reduction of Bone Turnover • Insufficient turnover • Accumulation of microdamage • Increased brittleness due to excessive mineralization • Excessive turnover • Increase in stress risers (weak zones) • Increase in perforations • Loss of connectivity Bone Strength Bone Turnover

  13. Adequacy of Suppressed bone resorption By bisphosphonates?

  14. Raloxifene Risedronate Alendronate Zoledronate Reduction Bone Turnover

  15. Preclinical Animal Studies • Marked reduction in • bone turnover • Increased bone • volume and density • Doubling of • mechanical strength • Fracture healing was • not impeded Risedronate Alendronate

  16. In Human … Using bone biopsy, With usual doses of the bisphosphonates Suppression of bone-forming surface by 60-90%

  17. Hypermineralization?

  18. How long Suppressed bone resorption By bisphosphonates?

  19. No Accumulation of Bone Turnover Urinary NTx BSAP

  20. Slight Gain of BMD 10 Years

  21. Number of Fractures in 10 yrs (FLEX) 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]

  22. Delayed/Absent Fracture Healing Bishphosphonate therapy in osteoporotic patients should be stopped after 5 years, pending additional research

  23. Normal Patients OB Osteoid OC Normal Patients

  24. ….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

  25. 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 beassociated with infection or local • trauma. • First report: 2003 • In many, occurrence after recent dental pathology, trauma, • or oral surgery.

  26. 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. Other 6% Prostate Ca. 5% Osteoporosis 13% MM 44% Breast Ca 32%

  27. 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

  28. 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 …

  29. Recommendations for ONJ

  30. 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?

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